PROJECT SUMMARY/ABSTRACT A primary goal of this application is to understand the molecular basis of environmental and epigenetic interactions that consequently influence inflammatory states underlying Type-2 diabetes mellitus (DM). Native Hawaiians and Pacific Islanders (NHs/PIs) experience a disproportionately higher prevalence and earlier onset of DM than other ethnic groups. The socioeconomic and lifestyle factors conferring NHs/PIs to the heightened prevalence of DM associate with altered global levels of DNA methylation, an epigenetic mechanism likely to play a major role in regulating the chronic low-grade systemic inflammation characteristic of DM. Indeed, inflammation has been shown to be associated with global DNA hypermethylation in peripheral blood mononuclear cells (PBMCs), independent of other risk factors for DM. Interestingly, differential DNA methylation at specific genomic loci in PBMCs exhibited changes at genes related to immune function and inflammatory pathways, which are associated with biomarkers of inflammation. However, the heterogeneity in cell type composition of PBMCs makes it difficult to determine how these observed differences in DNA methylation associate with inflammation. Monocytes play a central role in both acute and chronic inflammation, secreting various pro-inflammatory cytokines after stimulation with toll like receptor ligands, and are thus a major source of systemic inflammation. DNA methylation regulates the transcriptional levels of pro- inflammatory cytokines expressed by monocytes. Together, these studies suggest that the DNA methylation landscape of monocytes may be associated with inflammatory states of the cells, which may be altered in DM to correspond with inflammation. We seek to examine this relationship in NHs/PIs, which has never before been reported. We have collected preliminary data that form the basis for the hypothesis that compared to healthy individuals, monocytes from NHs/PIs diagnosed with DM exhibit a distinct DNA methylomic landscape, which conditions their heightened inflammatory response. To address this hypothesis, we propose to access our Multiethnic Cohort (MEC), from which we have detailed health information, and banked viably cryopreserved PBMCs and paired plasma biospecimens. We aim to (1) evaluate the relationships between insulin resistance, systemic inflammation, and ex vivo monocyte inflammatory activity in age- and sex-matched healthy (n=20) and DM-diagnosed (n=20) NHs/PIs, and (2) characterize and compare the DNA methylomes of these monocytes, following enrichment from PBMCs, using two independent yet complementary genome-wide approaches. We anticipate that these results will inform the extent to which the DNA methylomic landscape may condition monocyte inflammatory activity and how this associates with known risk factors for DM. This study will form the foundation for future work investigating the extent to which differences in monocyte function may be attributed to variability in DNA methylation between 5 distinct racial/ethnic groups in our MEC. Such studies would transform DM health disparities research to elucidate an epigenetic etiology.